The goal of this project is to develop a c-jun N-terminal kinase 2/3 (JNK2/3) inhibitor that may be used in the treatment of neurodegeneration in Parkinson's disease (PD). Development of a drug that prevents dopaminergic neurodegeneration would be first in class for halting progression of the disease and a clinical complement to existing medication used in symptomatic treatment of PD. We have assembled a team of biochemists, cell biologists, medicinal chemists, structural biologists, pharmacologists, analytical chemists, and behavioral pharmacologists with extensive pharmaceutical experience to execute this drug development program. In Aim 1 (years 1-2) we will optimize JNK2/3 inhibitors to select a preclinical development candidate. By the end of year 2 we anticipate having one or more compounds that: 1) are potent and selective JNK2/3 inhibitors, 2) promote primary dopaminergic neuronal survival, and 3) have good pharmacokinetic properties and brain penetration. This aim will be accomplished by utilizing medicinal chemistry and structure-based drug design supported by biochemical and cell-based assays, and pharmacokinetics to develop structure-activity-relationships (SAR). During Aim 2 (year 3) we will demonstrate efficacy in MPTP-mouse models of PD for greater than or equal to three compounds, demonstrate lack of interaction with human CYP450s, and evaluate five to ten compounds in preliminary toxicity studies. The reason for evaluating five to ten of our most promising compounds is to optimize the chance for clinical success and mitigate the risk of developing a single molecule that may fail in development. In Aim 3 (years 4-5) we will conduct Investigation New Drug enabling genotoxicity, safety pharmacology, and toxicology studies aimed at helping select a clinical candidate that has the best metabolic profile and widest therapeutic index. Collectively these studies are intended at generating a lead clinical candidate (and back ups) that have sufficient data to meet Food and Drug Administration standards to support up through Phase II human clinical trials in Parkinson's disease.